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Biomedical subjects

B Norris

Publications and source records attributed to B Norris.

At least 19 recordsLinked to original sources
PubMed1997

Decrease of tolerance to, and physical dependence on morphine by, glutamate receptor antagonists.

The effects of the non-competitive antagonists of the glutamate complex receptor, dizocilpine (MK 801) and ketamine and of the competitive antagonist CGP 39551 were examined on the induction of tolerance to morphine, the development of physical dependence and the expression of the abstinence syndrome to the opiate in mice. Morphine was administered in a single dose (300 mg/kg) of a slow release preparation. Dizocilpine (0.005 or 0.01 mg/kg given at 3, 12 and 24 h after the priming dose of morphine), ketamine (2, 4 or 8 mg/kg, 30 min before and 3, 6, 9 and 24 h after the priming dose) and DL-(E)-2-amino-4-methyl-5-phosphonopentanoate carboxy-ethylester (CGP 39551) (1.5 or 3 mg/kg, but not 6 or 12 mg/kg 30 min before and 12 and 24 h after the priming dose) reduced the intensity of tolerance to, and physical dependence on morphine. The drugs also reduced the intensity of the abstinence behaviour when given in a single dose, 30 min before (s.c.) naloxone (4 mg/kg)-precipitated withdrawal syndrome in mice chronically treated with morphine. Thus, the results of this study indicate that competitive and non-competitive NMDA receptor antagonists prevent morphine tolerance and decrease the development of physical dependence on the opiate in mice.

2-Amino-5-phosphonovalerate↗
PubMed1997

Influence of opiate tolerance and calcium channel antagonists on the antinociceptive effects of L-arginine and NG-nitro L-arginine.

1. The antinociceptive effects induced by L-arginine (L-Arg 300-600 mg sc) or NG-nitro-L-arginine (NOArg 20-70 mg sc) in mice were assessed by the hot-plate test. 2. The antinociception induced by both agents was antagonized by naloxone. L-Arg significantly reduced the effects of the largest doses of morphine (3, 5, and 10 mg/kg) or pentazocine (7.5, 15, and 30 mg/kg). 3. Morphine antagonized L-Arg-induced antinociception but did not change the responses to NOArg. 4. Diltiazem (10 mg/kg) or verapamil (10 mg/kg) decreased L-Arg antinociceptive responses, whereas the effects of NOArg were enhanced. 5. The antinociceptive effects of L-Arg and NOArg were also tested in mice rendered tolerant to morphine or pentazocine. Whereas the effect of L-Arg were lower in tolerant animals, the responses to NOArg were unchanged. 6. The results suggest the involvement of opiate mechanisms and NO synthesis in L-ARG-induced antinociception and a lesser influence of opiate mechanisms in the antinociception induced by NOArg.

Analgesia↗
PubMed1996

Influence of nitric oxide on transepithelial transport in toad skin: effects of cholinergic agents and morphine.

The effects induced by L-arginine (L-Arg) on the short-circuit current and potential difference of Pleurodema thaul skin were investigated. L-Arg, but not D-Arg significantly increased the short-circuit current and potential difference when applied to the serosal surface. The effects of L-Arg were antagonized by amiloride, NG-nitro-methyl-L-arginine (L-NAME) and by methylene blue. Carbachol and acetylcholine induced significant increases of both electrical parameters of the toad skin. These effects of the muscarinic cholinergic drugs were potentiated by a low concentration of L-Arg and antagonized by L-NAME or methylene blue. Carbachol and acetylcholine induced significant increases of both electrical parameters of the toad skin. These effects of the muscarinic cholinergic drugs were potentiated by a low concentration of L-Arg and antagonized by L-NAME or methylene blue. Addition of dibutyryl cyclic guanosyl monophosphate (db cGMP) or dibutyryl cyclic adenosine monophosphate (db cAMP) increased short-circuit current and potential difference. The effects of db cGMP, but not those of db cAMP were antagonized by L-NAME. The consecutive application of db cGMP and db cAMP induced additive effects. These results suggest that L-Arg increases transport in toad skin presumably acting through the formation of nitric oxide, which then stimulates cytoplasmic guanylate cyclase and leads to increased Na+ and K+ transport. The effects of L-Arg and carbachol were antagonized by acute application of morphine; however, a rebound response was observed when carbachol or noradrenaline were given after prolonged exposure of the skin to morphine, which suggests an adaptive response of the skin involving both cGMP and cAMP. Responses to both nucleotides were unchanged by morphine.

Acetylcholine↗
PubMed1996

Phase II study of the progesterone antagonist mifepristone in patients with untreated metastatic breast carcinoma: a National Cancer Institute of Canada Clinical Trials Group study.

PURPOSE: Mifepristone (RU486) is a progesterone receptor (PgR) antagonist that has been shown to be active in some preclinical hormone-dependent breast cancer tumor models and to produce a few responses in patients with pretreated metastatic disease in two small trials. This trial was designed to assess the response rate and toxic effects of mifepristone in a favorable group of women with PgR-positive recurrent breast cancer who had received no prior therapy. METHODS: Postmenopausal patients with PgR-positive, bidimensionally measurable disease were eligible provided they had received no other therapy for recurrence. Prior adjuvant hormonal treatment was permitted if a disease-free interval of at least 24 months had been observed. Mifepristone 200 mg was given daily and disease was reassessed every 4 weeks. Standard criteria for tumor response and toxic effects were used. RESULTS: A total of 28 patients were registered in the trial: all were eligible and assessable. Three partial responses were noted for an overall response rate of 10.7% (95% confidence interval [CI], 2% to 28%). Toxic effects were generally mild to moderate and consisted primarily of nausea, lethargy, anorexia, and hot flashes. CONCLUSION: Mifepristone had minimal activity in this optimal group of patients. While there may be reason to conduct some clinical studies with it in combination with antiestrogens on the basis of some preclinical work, our data do not support its use as a single agent in the management of breast cancer.

Aged↗
PubMed1996

An amino-terminal truncated progesterone receptor isoform, PRc, enhances progestin-induced transcriptional activity.

Previously we reported the identification of two unique progesterone receptor (PR) messenger RNA transcripts that encode a smaller PR isoform, termed the C-receptor (PRc). These two PR transcripts encode a protein that is N-terminally truncated, so that it lacks the first zinc finger of the DNA binding domain, but still contains a complete hormone binding region with sequences for dimerization and nuclear localization. We also have demonstrated the existence of a 60-kDa progestin-specific binding protein in progestin target cells using a monoclonal antibody directed to the C-terminus of PRs, suggesting that these two novel transcripts generate a truncated form of PR. In this paper, we address the hypothesis that the C-receptor arises from the initiation of translation of a methionine C-terminal to the methionine start sites that generate the larger 94-kDa A and 116-kDa B human PR isoforms. The studies shown here support the postulate that another downstream in-frame methionine within the PR-coding region can serve as a translation initiation site for the generation of a third PR protein. A partial PR complementary DNA, lacking the translation start sites for B- and A-receptors was translated in vitro. The synthetic protein product bound [3H]progestins and unlabeled progestins. The antiprogestin RU486 also competed for this binding. Transfection of this partial PR complementary DNA into PR-negative HeLa cells resulted in progestin-specific binding activity. Because the third PR isoform lacks the first zinc finger of the DNA binding domain, but contains sequences for dimerization, we reasoned that the C-receptor isoform would be transcriptionally in-active and not bind DNA directly. Surprisingly, however, in the presence of A- and/or B-receptors, we found that C-receptors can modulate the transcriptional activity of A- and/or B-receptors using a reporter gene. These studies emphasize that multiple receptor isoforms may have distinct biological properties, and that the truncated C-receptor may play a role in explaining some of the pleiotropic effects of progestins.

Antineoplastic Agents↗
PubMed1995

Diazepam induces tolerance in the isolated skin of Pleurodema thaul.

The effects of the long-term administration of diazepam on the potential difference and short-circuit current of the isolated skin of the toad Pleurodema thaul (P. thaul) were investigated. Diazepam applied in a concentration range of 4.6 x 10(-6) to 5.2 x 10(-5) M decreased both electrical parameters. This response was unaffected by flumazenil indicating that the action of diazepam is not induced through benzodiazepine receptors. Induction of tolerance to diazepam on its observed effects on potential difference and short-circuit current was obtained by the administration of a single dose of the drug in a slow release preparation. Skins tolerant to diazepam were also tolerant to the acute effects of verapamil on both electric parameters. Tolerance to diazepam effects was partly reversed by increasing Ca2+ concentration in the inner bathing solution. The results are consistent with a Ca2+ channel blocking effect of diazepam in the P. thaul skin.

Animals↗
PubMed1995

Diazepam decreases the response to the electrical stimulation of the nerve-skin preparation of the toad Caudiverbera caudiverbera.

1. The effect of diazepam was examined in the nerve skin preparation of the toad Caudiverbera caudiverbera. 2. Nerve stimulation was followed immediately by a transient increase in short-circuit current (SCC) and in the potential difference (PD), which consisted of a rapid and then a slow component. 3. Diazepam concentrations from 5.0 x 10(-5)M to 5.1 x 10(-4)M caused a dose-dependent block of both components to a 30% of their control values and also reduced the stimulatory responses to noradrenaline in this preparation. 4. Diazepam antagonized the potassium blocking effect of barium. 5. These results, based on electrophysiological and pharmacological evidence, are consistent with a calcium and sodium blocking effect of diazepam on the nerve skin junction of C. caudiverbera.

Adrenergic alpha-Agonists↗
PubMed1993

Pentachlorophenol (PCP) inhibits ion transport in the isolated toad cornea.

1. Active chloride transport from the stroma to the epithelial surface (tear side) accounts for 80% of the amphibian cornea short-circuit current (SCC). 2. The effect of pentachlorophenol (PCP, a wood preservative) on the bioelectric parameters of the toad Caudiverbera caudiverbera isolated cornea was studied. 3. PCP applied to the epithelial surface in the concentration range 0.3-4.3 microM caused a dose-dependent inhibition of the PD and of the SCC in 7 corneas. This inhibition was irreversible at all concentrations after several washouts. The agent had no effect when applied to the endothelial surface. 4. In 4 experiments the inhibitory effect was partly reversed by the addition of 1 microM calcium ionophore A-23187 to the epithelial surface. 5. It is concluded that PCP is an inhibitor of corneal active chloride transport and that this structure shows greater sensitivity to this agent than other tissues.

Animals↗
PubMed1993

Calcium channel blockers apparently decrease noradrenaline release from nerve-skin terminals in Caudiverbera caudiverbera.

1. The effects of three calcium channel blockers, verapamil, diltiazem and nifedipine were examined on the response of the skin neuroepithelial synapse of the toad Caudiverbera caudiverbera to electrical stimulation. 2. The stimulus induced a significant rise in potential difference (PD) and short-circuit current (SCC). The three calcium antagonists reduced the responses in a dose-dependent manner. The greatest reduction was induced by verapamil followed by diltiazem and nifedipine. 3. Amiloride treatment did not affect the responses to electrical stimulation, indicating that the response to nerve stimulation is not due to current flowing through sodium channels. 4. When the preparation was blocked by either of the three antagonists, the skin response to noradrenaline was not affected. 5. It may be concluded that verapamil, diltiazem or nifedipine reduce the release of noradrenaline at the neuroepithelial synapse of C. caudiverbera.

Amiloride↗
PubMed1992

Phase II study of oral menogaril as first line chemotherapy for advanced breast cancer: a National Cancer Institute of Canada Clinical Trials Group study.

The National Cancer Institute of Canada (NCIC) Clinical Trials Group conducted a phase II study of weekly oral menogaril as first-line therapy in 51 patients with incurable, metastatic or locally advanced breast cancer. While no prior chemotherapy for metastatic disease was permitted, prior adjuvant chemotherapy was allowed provided that no anthracycline or anthracene had been given. Forty-eight patients were evaluable for response. Two patients (4%) achieved complete remissions, 9 patients (19%) achieved partial remissions, 26 patients (54%) were stable and 11 patients (23%) failed. At the initial menogaril dose of 275 mg/m2 per week, 13 of 14 patients required a dose reduction and/or a treatment delay of one or more weeks. Therefore, the menogaril dose was reduced to 225 mg/m2 per week for the last 37 patients. At that those, 20 of 37 patients developed grade 3 or 4 granulocytopenia and 22 required dosage delays. At the initial starting dose, the average dose intensity actually delivered was 169 mg/m2 per week. At 225 mg/m2 the average dose intensity actually delivered was 197 mg/m2 per week. Toxic effects included mild to moderate nausea and vomiting, diarrhea, hair loss and occasional hyperpigmentation. In summary, menogaril is an anthracycline derivative that has modest activity when administered orally to minimally pretreated patients with breast cancer.

Adenocarcinoma↗
PubMed1991

Stimulatory effect of angiotensin II on electrolyte transport in canine tracheal epithelium.

1. The present study examines the effect of angiotensin11 (A11) on Cl- and Na+ transport in canine tracheal epithelium. 2. A concentration-dependent increase in the potential difference and in short-circuit current of the trachea was found. 3. Frusemide reduced values of Cl- dependent electrical parameters; net Cl- flux from serosa to mucosa accounted for 72% of total short-circuit current. 4. Frusemide, indomethacin and chlorpromazine blocked the stimulatory effect of A11. 5. These reactions show that A11 stimulates ion transport across the canine tracheal epithelium and suggest that two mechanisms may be proposed to explain the action of A11 on Cl- flux: (1) Ca(2+)-dependent increase in intracellular cAMP and (2) increase in Na(+)-2Cl2-K+ Cotransport activity.

Angiotensin II↗
PubMed1990

Quantitative structure-activity relationships of inhibitors of immune complex-induced inflammation: 1-phenyl-3-aminopyrazoline derivatives.

Quantitative structure-activity relationships (QSAR) of the 1-phenyl-3-aminopyrazoline analogues as inhibitors of immune complex-induced inflammation have been studied. The correlation suggests that the overall size of the phenyl substituents are of importance, and bulky groups have negative effects on potency. The negative steric effects are gradually increased from ortho to meta to para positions. The negative steric effects were sometimes altered by the electronic effects of the substituents. Electron-releasing groups on the phenyl ring increased potency, while electron-withdrawing groups decreased it. Ortho substituents, however, have unaccounted for additional deleterious effects described here with an indicator variable. The octanol-water partition coefficient (log P) and dissociation constants (pKa) of the 1-(m-trifluoromethylphenyl)-3-aminopyrazoline analogue have been experimentally determined.

Animals↗
PubMed1990

Use of nonradioactive 2-deoxyglucose to study compartmentation of brain glucose metabolism and rapid regional changes in rate.

A method is presented for measuring rapid changes in the rate of glucose phosphorylation in mouse brain with nonradioactive 2-deoxyglucose (DG). After times as short as 1 min after DG injection, the mouse is frozen rapidly, and selected brain regions are analyzed enzymatically for DG, 2-deoxyglucose 6-phosphate (DG6P), and glucose. The rate of glucose phosphorylation can be directly calculated from the rate of change in DG6P, the average levels of DG and glucose, and a constant derived from direct comparison of the rate of changes in glucose and DG6P after decapitation. Experiments with large brain samples provided evidence for a 2% per min loss of DG6P and at least two compartments differing in their rates of glucose metabolism, one rapidly entered by DG with glucose phosphorylation almost double that of average brain and another more slowly entered with a much lower phosphorylation rate. The method is illustrated by changes in phosphorylation within 2 min after injection of a convulsant or an anesthetic and over a 48-min time course with and without anesthesia. The sensitivity of the analytical methods can be amplified as much as desired by enzymatic cycling. Consequently, the method is applicable to very small brain samples. Examples are given for regions with volumes of 5 x 10(-4) microliters, but studies with samples as small as single large cell bodies are feasible.

Anesthesia, General↗
PubMed1990

Effect of microgravity on metabolic enzymes of individual muscle fibers.

Eleven enzymes were measured in individual fibers of soleus and tibialis anterior (TA) muscles from two flight and two control (synchronous) animals. There were five enzymes of glycogenolytic metabolism: phosphorylase, glucose-6-phosphate isomerase, glycerol-3-phosphate dehydrogenase, pyruvate kinase, and lactate dehydrogenase (group GLY); five of oxidative metabolism: citrate synthase, malate dehydrogenase, beta-hydroxyacyl-CoA dehydrogenase, 3-ketoacid CoA-transferase, and mitochondrial thiolase (group OX); and hexokinase, subserving both groups. Fiber size (dry weight per unit length) was reduced about 35% in both muscles. On a dry weight basis, hexokinase levels were increased 100% or more in flight fibers from both soleus and TA. Group OX enzymes increased 56-193% in TA without significant change in soleus. Group GLY enzymes increased an average of 28% in soleus fibers but underwent, if anything, a modest decrease (20%) in TA fibers. These changes in composition of TA fibers were those anticipated for a conversion of about half of the originally predominant fast glycolytic fibers into fast oxidative glycolytic fibers. Calculation on the basis of fiber length, rather than dry weight, gave an estimate of absolute enzyme changes: hexokinase was still calculated to have increased in both soleus and TA fibers, but only by 50 and 25%, respectively. Three of the OX enzymes were, on this basis, unchanged in TA fibers, but 3-ketoacid CoA-transferase and thiolase had still nearly doubled, whereas TA GLY enzymes had fallen about 40%. In soleus fibers, absolute levels of OX enzymes had decreased an average of 25% and GLY enzymes were marginally decreased.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1989

Inhibitors of immune complex-induced inflammation: 3-[1-(2-benzoxazolyl)hydrazino]propanenitrile derivatives.

The octanol-water partition coefficients (log P) and the dissociation constants (pKa) of 3-[1-(2-benzoxazolyl)hydrazino]propanenitrile analogues have been determined, and quantitative structure--activity relationships (QSAR) of the analogues as inhibitors of immune complex-induced inflammation have been studied. A significant correlation is observed between log P and pi substituent constants, and between pKa and inductive-field (F) and resonance (R) constants. The QSAR equations indicate that smaller substituents both at the 5-position and/or at the side chain tend to make the compound more potent, while an electron-withdrawing group at the side chain tends to make the compound less potent. The predicted potencies of 14 of 18 additional monosubstituted and all six disubstituted analogues agree reasonably well with the observed activities.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1988

Stimulatory effect of angiotensin II on the electric properties of the isolated toad skin.

In 1982 we showed that angiotensin II (Agt II) stimulates the bioelectric properties of the isolated toad skin and that this effect is blocked by pretreatment of the skin with indomethacine [J. B. Concha et al., IRCS Med. Sci. 10, 584 (1982)]. Ussing's technique and several inhibitors were used to continue this study on the isolated Pleurodema thaul skin. Serosal Agt II produced a dose-dependent increase in electrical parameters: a maximal concentration of 6 X 10(-6) M Agt II increased potential difference by 43 +/- 7.8% and short-circuit current by 51.5 +/- 7.7%. The responses were not affected by either alpha or beta blockers or by atropine. Indomethacine blocked responses to the calcium ionophore A23187 and to Agt II which were similar to each other. Additive effects of Agt II and of the calcium ionophore A23187 were found. No response to Agt II was obtained when Ca2+-free Ringer was used on the serosal side. Calcium channel blockers (nifedipine, verapamil, manganese), pentobarbitone and saralasin blocked the response to Agt II. This pharmacological evidence is in favour of the hypothesis that Agt II activates specific membrane receptors, leading to Ca2+ release and formation of prostaglandins which stimulate adenyl cyclase. This increases cAMP secretion, which in turn increases apical membrane permeability to sodium and enhances the active transport system.

Adrenergic alpha-Antagonists↗